PROCEDE AMELIORE DE PRODUCTION DE 4-(6-BROMOHEXYLOXY)-BUTYLBENZENE

IMPROVED PROCESS FOR THE MANUFACTURE OF 4-(6-BROMOHEXYLOXY)-BUTYLBENZENE

Abrégé français

La présente invention concerne un procédé amélioré de production de 4-(6-bromohexyloxy)-butylbenzène, consistant à mettre en réaction du 4-phénylbutanol avec du 1,6-dibromohexane en présence d'une base et d'un catalyseur par transfert de phase. Selon ce procédé, du 4-phénylbutanol est dosé dans un agent de dilution jusqu'à l'obtention d'un mélange constitué d'1,6-dibromohexane, d'une base, d'un catalyseur par transfert de phase et d'un agent de dilution. Ladite invention concerne également l'utilisation du 4-(6-bromohexyloxy)-butylbenzène ainsi produit dans la production de salmétérol de manière connue en soi.

Abrégé anglais

The invention relates to an improved method for producing 4-(6-bromohexyloxy)
butylbenzene
by reacting 4-phenylbutanol with 1,6-dibromohexane in the presence of a base
and a phase
transfer catalyst. 4-phenylbutanol is metered in a diluent to a mixture
consisting of
1,6-dibromohexane, a base, a phase transfer catalyst, and a diluent. Also
disclosed is the use of the
resulting 4-(6-bromohexyloxy) butylbenzene for producing salmeterol in a
previously known
manner.

Revendications

8
CLAIMS:
1. A process for preparing 4-(6-bromohexyloxy)-butylbenzene;
comprising: reacting 4-phenylbutanol with 1,6-dibromohexane in the presence of
a base and a phase transfer catalyst, wherein 4-phenylbutanol in a diluent is
metered into a mixture consisting of 1,6-dibromohexane, the base, the phase
transfer catalyst and the diluent.
2. The process according to claim 1, wherein powdered potassium
hydroxide is used as the base.
3. The process according to claim 1 or 2, wherein a
tetraalkylammonium or tetraalkylphosphonium salt is used as the phase transfer
catalyst.
4. The process according to claim 3, wherein a tetraalkylammonium
hydrogen sulphate is used as the phase transfer catalyst.
5. The process according to any one of claims 1 to 4, wherein an
aromatic hydrocarbon or an optionally halogenated aliphatic hydrocarbon is
used
as the diluent.
6. The process according to claim 5, wherein toluene or
dichloromethane is used as the diluent.
7. The process according to any one of claims 1 to 6, wherein the
reaction is carried out in a temperature range from -10°C to
+30°C.
8. The process according to any one of claims 1 to 7, wherein the
4-phenylbutanol is added within 10 to 240 minutes and the resulting reaction
mixture is stirred for a further 30 to 180 minutes.
9. The process according to any one of claims 1 to 8, wherein 0.75 to
2.5 equivalents of 1,6-dibromohexane are used, based on 1 equivalent of
4-phenylbutanol.
10. The process according to any one of claims 1 to 9, wherein 2.5 to
5.5 equivalents of the base are used, based on 1 equivalent of 4-
phenylbutanol.

9
11. The process according to any one of claims 1 to 10, wherein 0.01 to
0.5 equivalents of the phase transfer catalyst are used, based on 1 equivalent
of
4-phenylbutanol.
12. The process according to any one of claims 1 to 11, wherein the
mixture of 1,6-dibromohexane, the base, the phase transfer catalyst and the
diluent contains 1.5 to 4.0 parts by volume of the diluent, based on 1 part of
1,6-dibromohexane.
13. The process according to any one of claims 1 to 12, wherein the
mixture of 4-phenylbutanol and the diluent contains 1.5 to 10 parts by volume
of
the diluent, based on 1 part of 4-phenylbutanol.
14. The process according to any one of claims 1 to 13, wherein after
the reaction has ended water is added to the reaction mixture, the phases are
separated, the organic phase is washed with water, concentrated under reduced
pressure and the residue is fractionally distilled under high vacuum.
15. A process for preparing salmeterol, wherein the educt
4-(6-bromohexyloxy)-butylbenzene is prepared according to claim 1, 2, 3, 4, 5,
6,
7, 8, 9, 10, 11, 12, 13 or 14, and further processed to obtain salmeterol.

Description

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80448pct.210
Improved Process For The Manufacture Of 4-(6-Bromohexyloxy-But_ylbenzene
The present invention relates to an improved process for the manufacture of 4-
(6 -
bromohexyloxy)-butylbenzene by reacting 4-phenylbutanol with 1,6-dibromohexane
in the presence of a base and a phase transfer catalyst, and the use of the 4-
(6 -
bromohexyloxy)-butylbenzene thus prepared for producing salmeterol in a method
known per se.
Background to the Invention
4-(6-Bromohexyloxy)-butylbenzene is a valuable intermediate product for
preparing
the active substance salmeterol, which is used as a bronchodilator for
treating asthma
or chronic bronchitis.
According to the teaching of German patent application DE 34 14 752, 4 -(6-
bromohexyloxy)-butylbenzene is obtained by reacting 4-phenylbutanol with 1,6-
dibromohexane with a sodium hydride dispersion as base. For safety reasons it
is not
really possible to carry out production on an industrial scale using sodium
hydride
dispersions.
European patent application EP 1 132 373 describes a laboratory process for
producing 4-(6-bromohexyloxy)-butylbenzene in which a mixture consisting of
4-phenylbutanol, 1,6-dibromohexane, potassium hydroxide and tetrabutyl
ammonium
hydrogen sulphate is stirred for 20 hours at ambient temperature. However,
this
laboratory method cannot be carried out on an industrial scale as the reaction
is
strongly exothermic, leading to a sharp increase in the reaction temperature,
producing residues which are difficult to stir and secondary products
(elimination
products) which lower the yield.
The aim of the present invention is thus to provide a process which makes it
possible
to prepare 4-(6-bromohexyloxy)-butylbenzene in good yields on an industrial
scale

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2
while avoiding the drawbacks which occur with the processes known'from the
prior
art.
Detailed Description of the Invention
Surprisingly,. it has now been found that 4-(6-bromohexyloxy)-butylbenzene can
be
prepared in good yields and on an industrial scale by reacting 4-phenylbutanol
with
1,6-dibromohexane in the presence of a base and a phase transfer catalyst if 4-
phenylbutanol in a diluent is added to a mixture consisting of 1,6-
dibromohexane, a
base, a phase transfer catalyst and a diluent.
The invention thus relates to an improved process for preparing 4-(6-
bromohexyloxy)-butylbenzene by reacting 4-phenylbutanol with 1,6-dibromohexane
in the presence of a base and a phase transfer catalyst, in which 4-
phenylbutanol in a
diluent is metered into a mixture consisting of 1,6-dibromohexane, a base, a
phase
transfer catalyst and a diluent.
The invention further relates to the use of the 4-(6-bromohexyloxy)-
butylbenzene
prepared by the process according to the invention for producing salmeterol in
a
manner known per se.
Preferred embodiments of the process according to the invention are processes
wherein:
(A) the base used is an alkali metal hydroxide such as lithium hydroxide,
sodium hydroxide or potassium hydroxide, particularly powdered
potassium hydroxide;
(B) the phase transfer catalyst (PTC) used is a tetraalkylammonium or
tetraalkylphosphonium salt, wherein the alkyl groups may be identical or
different, such as for example salts of tetraoctylammonium,
methyltrioctylammonium, tetramethylammonium, tetraethylammonium,
tetrahexylammonium Aliquat 175 (tributylmethylammonium) or Aliquat*
336 (methyltrioctylammonium). Preferably, the PTC is a
* Trademark

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tetraalkylammonium halide, a tetraalkylammonium sulphate, a
tetraalkylammonium hydrogen sulphate, a tetraalkylammonium nitrate or a
tetraalkylammonium phosphate, more particularly a tetraalkylammonium
hydrogen sulphate, most preferably tetra-n-butylammonium hydrogen
sulphate.
The term "alkyl" as used above and hereinafter in connection with the phase
transfer
catalyst comprises straight-chain and branched alkyl groups with 1 to 8,
preferably 2
to 6, more particularly 4 carbon atoms. Thus, preferred alkyl groups are the
ethyl, n-
propyl, i-propyl, n-butyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, neo-
pentyl, n-hexyl
and 2-hexyl group. The n-butyl group is most particularly preferred.
Other preferred embodiments of the process according to the invention are
processes
wherein:
(C) the diluent used is an aromatic hydrocarbon, preferably benzene, toluene
or xylene, particularly toluene, or an optionally halogenated aliphatic
hydrocarbon, preferably dichloromethane, chloroform, carbon
tetrachloride or dichloroethane, particularly dichloromethane;
(D) the reaction is carried out in a temperature range from -10 C to +30 ,
preferably from 0 C to 28 C, particularly from 20 to 25 C;
(E) the 4-phenylbutanol is added within 10 to 240 minutes, preferably 15 to 60
minutes, and the resulting reaction mixture is stirred for a further 30 to
180, preferably 45 to 150 minutes;
(F) 0.75 to 2.5 equivalents, preferably 1.5 to 2.2 equivalents, more
particularly
about 2 equivalents of 1,6-dibromohexane are used, based on 1 equivalent
of 4-phenylbutanol;
(G) 2.5 to 5.5 equivalents, preferably 2.8 to 5.2 equivalents, more
particularly
3.0 to 4.0 equivalents of base are used, based on 1 equivalent of
4-phenylbutanol;

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(H) 0.01 to 0.5 equivalents, preferably 0.02 to 0.2 equivalents, more
particularly 0.05 to 0.15 equivalents of phase transfer catalyst are used
based on I equivalent of 4-phenylbutanol;
(I) the mixture of 1,6-dibromohexane, a base, a phase transfer catalyst and a
diluent contains 1.5 to 4.0 parts by volume, preferably 2.0 to 3.0 parts by
volume, more particularly 2.2 to 2.8 parts by volume of diluent, based on 1
part by volume of 1,6-dibromoehexane;
(J) the mixture of 4-phenylbutanol and diluent contains 1.5 to 10 parts by
volume, preferably 2.0 to 6.0 parts by volume, more particularly 3.0 to 5.0
parts by volume of diluent, based on 1 part by volume of 4 -phenylbutanol;
(K) after the reaction has ended water is added to the reaction mixture, the
phases are separated, the organic phase is washed with water, concentrated
under reduced pressure and the residue is fractionally distilled under a high
vacuum.
In a particularly preferred embodiment 1 equivalent of 4 -phenylbutanol in
about
twice the volume of toluene is metered, within 10 to 60 minutes, into a
mixture of
about 2 equivalents of 1,6-dibromohexane, 3 to 5 equivalents of KOH, about 0.1
equivalents of tetra-n-butylammonium hydrogen sulphate and 4 to 6 times the
volume of toluene, based on the volume of 4-phenylbutanol, at a temperature
between 20 and 30 C, with stirring. After it has all been added the mixture is
rinsed with toluene and stirred for 90 to 360, preferably about 180 to 240
minutes
at a temperature between 20 and 30 C. Then water is added, the organic phase
is
separated off and washed with water. The organic phase is concentrated and the
residue is fractionally distilled under a high vacuum.
Further advantageous aspects of the procedure according to the invention are
the
high space-time yield of the present process as well as the high yield and
purity of
4-(6-bromohexyloxy)-butylbenzene, which can be further processed directly or
after distillation to form salmeterol.

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Starting from the 4-(6-bromohexyloxy)-butylbenzene prepared by the process
according to the invention, salmeterol is prepared in a manner known per se as
described, for example, in DE 34 14 752 or EP 1 132 373.
The following Examples serve to illustrate some processes carried out by way
of
example for preparing 4-(6-bromohexyloxy)-butylbenzene. They are to be
regarded merely as possible procedures described by way of example without
restricting the invention to their content.
Example 1 - 4-(6-Bromohexyloxy)-butylbenzene
At a temperature between 20 and 25 C, with stirring, a mixture of 247.5 ml
(1.65
mol) of 4-phenylbutanol and 500 ml of toluene are added within 45 minutes to a
mixture of 509.6 ml (3.3 mol) of 1,6 -dibromohexane, 402 g of powdered (6.1
mol
KOH) caustic potash, 5.6 g (0.165 mol) tetra-n-butylammonium hydrogen
sulphate and 1250 ml of toluene.
After it has all been added, the mixture is rinsed with 125 ml of tolene and
stirred
for a further 2.5 hours at a temperature between 20 and 25 C. Then 1875 ml of
water are added, the organic phase is separated off and washed twice with 1250
ml of water. The organic phase is evaporated down under reduced pressure using
the rotary evaporator and the residue is fractionally distilled under a high
vacuum
(p < 0.1 mbar). 408.5 g (79% of theory) of the title compound are obtained as
a
colourless oil.

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Example 2 - 4-(6-bromohexyloxy)-butylbenzene
A mixture of 10 ml (0.0655 mol) of 4-phenylbutanol and 20 ml of toluene is
added within 15 minutes, with stirring, to a mixture of 20.2 ml (0.131 mol) of
1,6-
dibromohexane, 16 g of powdered (0.242 mol KOH) caustic potash, 2.2 g (0.0066
mol) tetra-n-butylammonium hydrogen sulphate and 50 ml of toluene, at a
temperature between 25 and 30 C. After it has all been added the mixture is
rinsed with 5 ml of toluene and stirred for 2 hours at a temperature between
25
and 30 C. Then 75 ml of water are added, the organic phase is separated off
and
washed twice with 50 ml of water. The organic phase is concentrated under
reduced pressure using the rotary evaporator and the residue is fractionally
distilled under a high vacuum (p < 0.1 mbar). 14.62 g (71% of theory) of the
title
compound are obtained as a colourless oil.
Comparison Example 1 - 4-(6-bromohexyloxy)-butylbenzene (corresponding to
EP 1 132 373)
To a mixture of 5 ml (0.0323 mol) of 4-phenylbutanol and 10.1 ml (0.0657 mol)
of 1,6-dibromohexane are added, with stirring, 8g of powdered (0.121 mol of
KOH) caustic potash, whereupon the temperature rises to about 30 C. Then 1.1 g
(0.0033 mol) of tetra-n-butylammonium hydrogen sulphate are added, whereupon
the temperature rises to about 65 C.
After it has all been added the mixture is stirred for 20 hours at ambient
temperature. The reaction mixture is filtered, the filtrate is taken up in 50
ml of
diethylether and 50 ml of water are added. The organic phase is separated off
and
dried. The organic phase is evaporated down under reduced pressure using the
rotary evaporator and the residue is fractionally distilled under a high
vacuum (p <
0.1 mbar). 5.8 g (56% of theory) of the title compound are obtained as a
colourless oil.

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Comparison Example 2 - 4-(6-bromohexyloxy)-butylbenzene
To a mixture of 20.2 ml (0.131 mol) of 1,6-dibromohexane, 16 g of powdered
(0.242 mol KOH) caustic pot acid and 2.2 g (0.0066 mol) of tetra-n-
butylammonium hydrogen sulphate are added 10 ml (0.0655 mol) of 4-
phenylbutanol within 15 minutes, with stirring, at a temperature between 20
and
30 C. The reaction was spontaneously exothermic and the temperature could
hardly be controlled. Towards the end of the addition, hard lumps were formed
and the reaction mixture was impossible to stir.